Cytokine regulation of intestinal epithelial restitution

项目总结 炎症性肠病(IBD)，包括克罗恩病和溃疡性结肠炎，是一种慢性疾病 胃肠道的炎症性疾病。IBD在美国困扰着近150万人。 IBD的确切原因尚不清楚，但通常被认为与调节失调的宿主免疫有关 遗传易感个体对共生微生物的反应。肿瘤坏死因子，a 主要的免疫细胞因子，在疾病过程中起着核心作用。虽然抗肿瘤坏死因子疗法是 对于许多IBD患者的药物治疗方案，越来越多的证据表明，完全阻断肿瘤坏死因子 从长远来看，对许多人来说，发出信号并不合适。例如，大多数接受抗肿瘤坏死因子治疗的患者 生物制剂在5年内停止对治疗的反应。我们和其他人已经证明了肿瘤坏死因子信号 通过其特征较少的受体，TNFR2在结肠修复方面具有许多有益的功能 上皮屏障，IBD的关键缓解方面，以及对免疫细胞的调节，包括细胞毒 (CD8+)T淋巴细胞和调节性T细胞。本申请将对这些新颖的观察结果进行后续处理 探讨肿瘤坏死因子受体2 S对CD8+T细胞和结肠上皮干细胞保护作用的机制 细胞群在结肠损伤和炎症的背景下。具体来说，我们将：1)确定 TNFR2调节CD8+T细胞在结肠炎中致病的机制，2)阐明 TNFR2在调节CD8+T细胞亚群及其结肠定位中的作用 上皮肿瘤坏死因子受体2对结肠上皮干细胞动力学和粘膜愈合的影响。这些研究将揭示 可能构成IBD病理生理学基础的重要细胞和分子模式。

PROJECT SUMMARY Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is a chronic inflammatory disorder of the gastrointestinal tract. IBD afflicts nearly 1.5 million people in the United States. The exact causes of IBD are unknown, but they are thought to generally involve dysregulated host immune responses to commensal microorganisms in genetically susceptible individuals. Tumor necrosis factor (TNF), a major immune cytokine, has a central role in the disease process. While anti-TNF therapies are a part of the medical regimen for many IBD patients, there is mounting evidence that the complete blockade of TNF signaling is not appropriate in the long-term for many. For example, most patients treated with anti-TNF biologics stop responding to the therapy within 5 years. We and others have demonstrated that TNF signaling through its lesser-characterized receptor TNFR2 has many beneficial functions on the repair of the colonic epithelial barrier, a crucial mitigating aspect of IBD, and on the regulation of immune cells including cytotoxic (CD8+) T lymphocytes and regulatory T cells. This application will follow-up on these novel observations to explore the mechanisms that underlie TNFR2's protective effects on CD8+ T cells and colonic epithelial stem cell populations in the setting of colonic injury and inflammation. Specifically, we will: 1) determine the mechanisms by which TNFR2 regulates the pathogenicity of CD8+ T cells in colitis, 2) elucidate the role of TNFR2 in regulation of CD8+ T cell subpopulations and their colonic localization, and 3) define the role of epithelial TNFR2 on colonic epithelial stem cell dynamics and mucosal healing. These studies will reveal important cellular and molecular patterns that may underlie the pathophysiology of IBD.